First live birth before surgical verification of endometriosis-a nationwide register study of 18 324 women.

STUDY QUESTION: Do women with endometriosis have lower first live birth rate before surgical diagnosis than women without verified endometriosis? SUMMARY ANSWER: Compared to reference women, the incidence of first live birth was lower in women prior to surgical verification of endometriosis irrespective of the type of endometriosis. WHAT IS KNOWN ALREADY: Endometriosis is associated with pain and reduced fertility. The mechanism of infertility is partly explained by anatomical, endocrinological, and immunological changes. Over the past decades, the treatment of both endometriosis and infertility has evolved. Knowledge of fertility far before surgical diagnosis of endometriosis in large cohorts and of different types of endometriosis has been lacking. The diagnostic delay of endometriosis is long, 6-7 years. STUDY DESIGN, SIZE, DURATION: Retrospective population-based cohort study focused on the time period before the surgical verification of endometriosis. All women with surgical verification of endometriosis in 1998-2012 were identified from the Finnish Hospital Discharge Register and the reference cohort from the Central Population Register. Data on deliveries, gynecological care, and sociodemographic factors before the surgical diagnosis were gathered from Finnish national registers maintained by the Finnish Institute for Health and Welfare, the Digital and Population Data Services Agency, and Statistics Finland. PARTICIPANTS/MATERIALS, SETTING, METHODS: All women aged 15-49 years at the time of surgical verification of endometriosis (ICD-10: N80.1-N80.9) in Finland during 1998-2012 were identified (n = 21 620). Of them, we excluded women born in 1980-1999 due to the proximity of the surgical diagnosis (n = 3286) and women left without reference (n = 10) for the final endometriosis cohort of 18 324 women. From the final cohort, we selected sub-cohorts of women with isolated diagnosis of ovarian (n = 6384), peritoneal (n = 5789), and deep (n = 1267) endometriosis. Reference women were matched by age and residence and lacked registered clinical or surgical diagnosis of endometriosis (n = 35 793). The follow-up started at the age of 15 years and ended at the first birth, sterilization, bilateral oophorectomy, hysterectomy, or until the surgical diagnosis of endometriosis or corresponding index day-whichever came first. Incidence rate (IR) and the incidence rate ratio (IRR) of first live birth before the surgical verification of endometriosis with corresponding CIs were calculated. In addition, we reported the fertility rate of parous women (the number of all children divided by the number of parous women in the cohort) until the surgical verification of endometriosis. The trends in first births were analysed according to the women's birth cohort, type of endometriosis, and age. MAIN RESULTS AND THE ROLE OF CHANCE: Surgical diagnosis of endometriosis was set at the median age of 35.0 years (IQR 30.0-41.4). Altogether 7363 women (40.2%) with endometriosis and 23 718 (66.3%) women without endometriosis delivered a live born infant before the index day (surgery). The IRs of the first live birth per 100 person-years were 2.64 (95% CI 2.58-2.70) in the endometriosis cohort and 5.21 (95% CI 5.15-5.28) in the reference cohort. Between the endometriosis sub-cohorts, the IRs were similar. The IRR of the first live birth was 0.51 (95% CI 0.49-0.52) between the endometriosis and reference cohorts. Fertility rate per parous woman before the surgical diagnosis was 1.93 (SD 1.00) and 2.16 (SD 1.15) in the endometriosis and reference cohorts (P < 0.01). The median age at the first live birth was 25.5 (IQR 22.3-28.9) and 25.5 (IQR 22.3-28.6) years (P = 0.01), respectively. Between the endometriosis sub-cohorts, women in the ovarian sub-cohort were the oldest at the time of surgical diagnosis with the median age of 37.2 years (IQR 31.4-43.3), (P < 0.001). Altogether 44.1% (2814) of the women with ovarian, 39.4% (2282) with peritoneal, and 40.8% (517) with deep endometriosis delivered a live born infant before the diagnosis. IRRs between the endometriosis sub-cohorts did not differ. Fertility rate per parous woman was lowest, 1.88 (SD 0.95), in the ovarian sub-cohort compared to 1.98 (SD 1.07) in the peritoneal and 2.04 (SD 0.96) in deep endometriosis (P < 0.001). Women with ovarian endometriosis were oldest at first live birth compared to women in other sub-cohorts with a median age of 25.8 years (IQR 22.6-29.1) (P < 0.001). Cumulative distributions of first live birth were presented according to age at first live birth and birth cohorts of the participants. LIMITATIONS, REASONS FOR CAUTION: The increasing age at first live birth, increasing practice of clinical diagnostics, conservative treatment of endometriosis, a possible effect of coexisting adenomyosis, and use of artificial reproductive treatments should be considered when assessing the results. In addition, the study is limited due to possible confounding effects of socioeconomic factors, such as level of education. It should be noted that, in this study, we assessed parity only during the years preceding the surgical verification of endometriosis. WIDER IMPLICATIONS OF THE FINDINGS: The need for early diagnosis and relevant treatment of endometriosis appears clear given the impairment of fertility prior to its surgical verification. STUDY FUNDING/COMPETING INTEREST(S): The study was funded by the Hospital District of Helsinki and Uusimaa and by Finska Läkaresällskapet. The authors report no conflicts of interest. All authors have completed the ICMJE Disclosure form. TRIAL REGISTRATION NUMBER: N/A.

Ethinylestradiol in combined hormonal contraceptive has a broader effect on serum proteome compared with estradiol valerate: a randomized controlled trial.

STUDY QUESTION: Does an estradiol-based combined oral contraceptive (COC) have a milder effect on the serum proteome than an ethinylestradiol (EE)-based COC or dienogest (DNG) only? SUMMARY ANSWER: The changes in serum proteome were multifold after the use of a synthetic EE-based COC compared to natural estrogen COC or progestin-only preparation. WHAT IS KNOWN ALREADY: EE-based COCs widely affect metabolism, inflammation, hepatic protein synthesis and blood coagulation. Studies comparing serum proteomes after the use of COCs containing EE and natural estrogens are lacking. STUDY DESIGN, SIZE, DURATION: This was a spin-off from a randomized, controlled, two-center clinical trial. Women (n = 59) were randomized to use either EE + DNG, estradiol valerate (EV) + DNG or DNG only continuously for 9 weeks. PARTICIPANTS/MATERIALS, SETTING, METHODS: Participants were healthy, young, white volunteer women. Serum samples were collected before and after 9 weeks of hormonal exposure. Samples from 44 women were available for analysis (EE + DNG n = 14, EV + DNG n = 16 and DNG only n = 14). Serum proteins were analyzed by quantitative, discovery-type label-free proteomics. MAIN RESULTS AND THE ROLE OF CHANCE: Altogether, 446 proteins/protein families with two or more unique peptides were detected and quantified. The number of proteins/families that altered over the 9-week period within the study groups was 121 for EE + DNG and 5 for EV + DNG, while no changes were detected for DNG only. When alterations were compared between the groups, significant differences were detected for 63 proteins/protein families, of which 58 were between the EE + DNG and EV + DNG groups. The most affected functions during the use of EE + DNG were the complement system, acute phase response signaling, metabolism and the coagulation system. The results were validated by fetuin-B and cortisol-binding globulin ELISA and sex hormone-binding globulin immunoassay. LARGE SCALE DATA: Data are available via ProteomeXchange with identifiers PXD033617 (low abundance fraction) and PXD033618 (high abundance fraction). LIMITATIONS, REASONS FOR CAUTION: The power analysis of the trial was not based on the proteomic analysis of this spin-off study. In the future, targeted proteomic analysis with samples from another trial should be carried out in order to confirm the results. WIDER IMPLICATIONS OF THE FINDINGS: The EE-based COC exerted a broader effect on the serum proteome than the EV-based COC or the DNG-only preparation. These results demonstrate that the effects of EE in COCs go far beyond the established endpoint markers of estrogen action, while the EV combination is closer to the progestin-only preparation. The study indicates that EV could provide a preferable option to EE in COCs in the future and signals a need for further studies comparing the clinical health outcomes of COCs containing EE and natural estrogens. STUDY FUNDING/COMPETING INTEREST(S): Funding for this researcher-initiated study was obtained from the Helsinki University Hospital research funds, the Hospital District of Helsinki and Uusimaa, the Sigrid Juselius Foundation, the Academy of Finland, the Finnish Medical Association, the University of Oulu Graduate School, the Emil Aaltonen Foundation, the Swedish Cultural Foundation in Finland, the Novo Nordisk Foundation, Orion Research Foundation and the Northern Ostrobothnia Regional Fund. The funders had no role in study design, data collection and analysis, publishing decisions or manuscript preparation. T.P. has received honoraria for lectures, consultations and research grants from Exeltis, Gedeon Richter, MSD, Merck, Pfizer, Roche, Stragen and Mithra Pharmaceuticals. O.H. occasionally serves on advisory boards for Bayer AG and Gedeon Richter and has designed and lectured at educational events for these companies. The other authors have nothing to disclose. O.H. occasionally serves on advisory boards for Bayer AG and Gedeon Richter and has designed and lectured at educational events for these companies. The other authors have nothing to disclose. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov NCT02352090. TRIAL REGISTRATION DATE: 27 January 2015. DATE OF FIRST PATIENT'S ENROLMENT: 1 April 2015.

Incidence of lichen sclerosus and subsequent causes of death: a nationwide Finnish register study.

OBJECTIVE: To assess the incidence of lichen sclerosus (LS) in women and the all-cause and cause-specific mortality of women with LS. DESIGN: Population-based descriptive study. SETTING: Finland. POPULATION: All Finnish women, including 7790 women diagnosed with LS during the period 1969-2012. METHODS: Information gathered from the Finnish Hospital Discharge Register on women with LS was combined with dates and causes of death from Statistics Finland and the Finnish Cancer Registry. Population statistics are from Statistics Finland. MAIN OUTCOME MEASURES: Crude and age-adjusted incidence rates of LS and standardised mortality ratios (SMRs). RESULTS: The incidence rate of LS adjusted for age (European Standard Population) increased from 14 per 100 000 woman-years in 2003 to 22 per 100 000 woman-years in 2010-2012. The age-specific incidence rate was highest in postmenopausal women (24-53 per 100 000) but was also elevated in girls aged 5-9 years (seven per 100 000). The all-cause mortality of women with LS was lower than in the general female population (SMR 0.84, 95% CI 0.78-0.90), mostly as a result of decreased mortality from circulatory diseases (SMR 0.80, 95% CI 0.72-0.89) and dementia and Alzheimer's disease (SMR 0.75, 95% CI 0.62-0.88). The cancer mortality equalled that of the population, but the vulvar cancer mortality was increased (SMR 28.1, 95% CI 19.3-39.4). CONCLUSIONS: Lichen sclerosus is a common disease of elderly women. The overall mortality is decreased whereas the mortality as a result of vulvar cancer is increased. TWEETABLE ABSTRACT: The likelihood of getting LS by age 80 years is 1.6%. The mortality of women with LS is reduced compared with that of the population.

Mortality of midlife women with surgically verified endometriosis-a cohort study including 2.5 million person-years of observation.

STUDY QUESTION: Is all-cause and cause-specific mortality increased among women with surgically verified endometriosis? SUMMARY ANSWER: The all-cause and cause-specific mortality in midlife was lower throughout the follow-up among women with surgically verified endometriosis compared to the reference cohort. WHAT IS KNOWN ALREADY: Endometriosis has been associated with an increased risk of comorbidities such as certain cancers and cardiovascular diseases. These diseases are also common causes of death; however, little is known about the mortality of women with endometriosis. STUDY DESIGN, SIZE, DURATION: A nationwide retrospective cohort study of women with surgically verified diagnosis of endometriosis was compared to the reference cohort in Finland (1987-2012). Follow-up ended at death or 31 December 2014. During the median follow-up of 17 years, 2.5 million person-years accumulated. PARTICIPANTS/MATERIALS, SETTING, METHODS: Forty-nine thousand nine hundred and fifty-six women with at least one record of surgically verified diagnosis of endometriosis in the Finnish Hospital Discharge Register between 1987 and 2012 were compared to a reference cohort of 98 824 age- and municipality-matched women. The age (mean ± standard deviation) of the endometriosis cohort was 36.4 ± 9.0 and 53.6 ± 12.1 years at the beginning and at the end of the follow-up, respectively. By using the Poisson regression models the crude and adjusted all-cause and cause-specific mortality rate ratios (MRR) and 95% confidence intervals (CI) were assessed. Calendar time, age, time since the start of follow-up, educational level, and parity adjusted were considered in the multivariate analyses. MAIN RESULTS AND THE ROLE OF CHANCE: A total of 1656 and 4291 deaths occurred in the endometriosis and reference cohorts, respectively. A lower all-cause mortality was observed for the endometriosis cohort (adjusted MRR, 0.73 [95% CI 0.69 to 0.77])-there were four deaths less per 1000 women over 10 years. A lower cause-specific mortality contributed to this: the adjusted MRR was 0.88 (95% CI 0.81 to 0.96) for any cancer and 0.55 (95% CI 0.47 to 0.65) for cardiovascular diseases, including 0.52 (95% CI 0.42 to 0.64) for ischemic heart disease and 0.60 (95% CI 0.47 to 0.76) for cerebrovascular disease. Mortality due to alcohol, accidents and violence, respiratory, and digestive disease-related causes was also decreased. LIMITATIONS, REASONS FOR CAUSATION: These results are limited to women with endometriosis diagnosed by surgery. In addition, the study does not extend into the oldest age groups. The results might be explained by the characteristics and factors related to women's lifestyle, and/or increased medical attention and care received, rather than the disease itself. WIDER IMPLICATIONS OF THE FINDINGS: These reassuring data are valuable to women with endometriosis and to their health care providers. Nonetheless, more studies are needed to address the causality. STUDY FUNDING/COMPETING INTEREST: This research was funded by the Hospital District of Helsinki and Uusimaa and The Finnish Medical Foundation. None of the authors report any competing interest in relation to the present work; all the authors have completed the disclosure form.

Trends in the incidence, rate and treatment of miscarriage-nationwide register-study in Finland, 1998-2016.

STUDY QUESTION: What changes have occurred in the incidence of miscarriage, its treatment options, and the profile of the women having miscarriages in Finland between 1998 and 2016? SUMMARY ANSWER: The annual incidence of registry-identified miscarriage has declined significantly between 1998 and 2016, and non-surgical management has become the dominant treatment. WHAT IS KNOWN ALREADY: Miscarriage occurs in 8-15% of clinically recognized pregnancies and in ~30% of all pregnancies. Increasing maternal age is associated with an increasing risk of miscarriage. The treatment of miscarriage has evolved significantly in recent years: previously, surgical evacuation of the uterus was the standard of care, but nowadays medical and expectant management are increasingly used. STUDY DESIGN, SIZE, DURATION: We conducted a nationwide retrospective cohort study of 128 381 women that had experienced a miscarriage that was managed in public healthcare between 1998 and 2016 in Finland. PARTICIPANTS/MATERIALS, SETTING, METHODS: We used the National Hospital Discharge Registry for the data. Women aged 15-49 years that had experienced their first miscarriage during the follow-up period and had miscarriage-related diagnoses during their admission to public hospital were included in the study. Miscarriages were defined by the 10th Revision of the International Statistical Classification of Diseases and related Medical Problems (ICD-10) diagnostic codes O02*, O03* and O08*. Women with ectopic, molar and continuing pregnancies and induced abortions were excluded. Treatment was divided into surgical and non-surgical treatment using the surgical procedure codes. MAIN RESULTS AND THE ROLE OF CHANCE: The annual incidence of registry-identified miscarriage has declined from 6.8/1000 15-49-year-old women in 1998 to 5.0/1000 in 2016 (P < 0.001). Also, the incidence rate of registry-identified miscarriage (i.e. the proportion of miscarriages of registry-identified pregnancies [i.e. deliveries, induced abortions, and miscarriages]) has declined from 112/1000 15-49-year-old pregnant women in 1998 to 83/1000 in 2016 (P < 0.001). The largest decrease in this proportion occurred among women over 40 years of age, among whom 26.5% of registry-identified pregnancies in 1998 ended in miscarriage compared to that of 16.4% in 2016. The proportion of missed abortion has increased (30.3 to 38.8%, P < 0.001) whereas that of blighted ovum has decreased (25.4 to 12.8%, P < 0.001). The proportion of registry-identified miscarriages seen among nulliparous women has increased from 43.7 to 49.6% (P < 0.001). Mean age at the time of miscarriage remained at 31 years throughout the study. Altogether, 29% of all miscarriages were treated surgically and 71% underwent medical or expectant management. The proportion of surgical management has decreased from 38.0 to 1.6% for spontaneous abortion, from 60.7 to 9.4% for blighted ovum and 70.9 to 11.2% for missed abortion between 1998 and 2016. LIMITATIONS, REASONS FOR CAUTION: This study includes only women with registry-identified pregnancies, i.e. women who were treated in public hospitals. However, the number of women treated elsewhere is presumed to be small. Neither can this study estimate the number of women having spontaneous miscarriage with no hospital contact. WIDER IMPLICATIONS OF THE FINDINGS: Both the annual incidence and incidence rate of miscarriage of all registry-identified pregnancies has decreased, and non-surgical management has become the standard of care. These findings are of value when planning allocation of healthcare resources and at individual level considering fertility and miscarriage questions. We speculate that improving ultrasound diagnostics explains the increasing proportion of missed abortion relative to other types of miscarriage. More investigation is needed to examine potential risk factors, complications and morbidity associated with miscarriages. STUDY FUNDING/COMPETING INTEREST(S): This study was funded by the research funds of the Helsinki and Uusimaa hospital system, by a personal grant from Viipurin Tuberkuloosisäätiö to R.L. and by a personal grant from The Finnish Cultural Foundation to N.H. The authors have no conflicts of interest to declare.

Comprehensive nationwide analysis of mother-to-child HIV transmission in Finland from 1983 to 2013.

HIV-positive children are still born in Europe despite low mother-to-child transmission (MTCT) rates. We aimed to clarify the remaining barriers to the prevention of MTCT. By combining the national registers, we identified all women living with HIV delivering at least one child during 1983-2013. Of the 212 women delivering after HIV diagnosis, 46% were diagnosed during the pregnancy. In multivariate analysis, age >30 years (P = 0.001), sexual transmission (P = 0.012), living outside of the metropolitan area (P = 0.001) and Eastern European origin (P = 0.043) were risk factors for missed diagnosis before pregnancy. The proportion of immigrants increased from 18% before 1999 to 75% during 2011-2013 (P < 0.001). They were diagnosed during the pregnancy equally to natives and achieved similar, good treatment results. No MTCT occurred when the mother was diagnosed before the delivery. In addition, 12 women had delivered in 2 years prior their HIV diagnosis, most before implementation of the national screening of pregnant women. Three of these children were infected, the last one in 2000. Our data demonstrate that complete elimination of MTCT is feasible in a high-income, low-prevalence country. This requires ongoing universal screening in early pregnancy and easy access to antiretroviral therapy to all HIV-positive people.

Intrauterine adhesions following an induced termination of pregnancy: a nationwide cohort study.

OBJECTIVE: Intrauterine adhesions (IUAs) are a problematic complication after termination of pregnancy, but their incidence is unknown. Our objective was to assess the incidence of IUAs following induced termination of pregnancy and the risk factors for IUAs. DESIGN: Retrospective cohort study. SETTING: A nationwide registry study. SAMPLE: All women undergoing induced termination of pregnancy (n = 80 015) in Finland between 2000 and 2008. METHODS: The data were retrieved from the Finnish Abortion Registry and the Hospital Discharge Registry. The diagnosis of IUAs or complications was based on the diagnostic codes (International Statistical Classification of Diseases and Related Health Problems 10th Revision, ICD-10) and operative codes according to the Nordic Medico-Statistical Committee (NOMESCO) Classification of Surgical Procedures (NCSP). IUAs were defined as ICD-10 code N85.6 or operative code LCG02. A subanalysis of IUA cases and five matched controls was performed. MAIN OUTCOME MEASURES: The incidence of and risk factors for IUAs. RESULTS: A total of 12 (1.5 per 10 000) IUA diagnoses were identified from 79 960 eligible induced terminations of pregnancy. The rate of IUAs was 1.5 and 2.0 cases per 10 000 terminations of pregnancy following medically and surgically induced termination of pregnancy, respectively (P = 0.19). In a subgroup analysis of IUA cases and five matched controls, surgical treatment of the remaining products of conception following termination of pregnancy significantly increased the risk of IUAs (odds ratio, OR 5.50; 95% confidence interval, 95% CI 1.46-20.79; P = 0.012). CONCLUSION: IUAs that require further treatment are rare after an induced termination of pregnancy. Surgical evacuation following medical or surgical termination of pregnancy was a risk factor for the diagnosis of IUAs. These results suggest that trauma to a recently pregnant uterus is an important risk factor for IUAs. TWEETABLE ABSTRACT: IUA is rare after induced termination of pregnancy (iTOP), but surgical evacuation is a risk factor for IUAs.

Expulsions and adverse events following immediate and later insertion of a levonorgestrel-releasing intrauterine system after medical termination of late first- and second-trimester pregnancy: a randomised controlled trial.

OBJECTIVES: To compare expulsions and adverse events (AEs) between immediate and delayed insertion of a levonorgestrel-releasing intrauterine system (LNG-IUS) following medical termination of pregnancy (MTOP). DESIGN: Randomised controlled trial. SETTING: Helsinki University Hospital, Finland, January 2013-December 2014. POPULATION: Cohorts of 102 (gestational age 64-84 days, late first trimester) and 57 (gestational age 85-140 days, second trimester) women requesting MTOP and LNG-IUS contraception. METHODS: LNG-IUS insertion occurred immediately (same day) or 2-4 weeks following MTOP. Follow-up visits were at 2-4 weeks, 3 months, and 1 year. MAIN OUTCOME MEASURES: LNG-IUS expulsion by 3 months and 1 year. AEs and bleeding profiles within 3 months. RESULTS: Following late first-trimester MTOP the LNG-IUS expulsion rates by 3 months were 14 (27.5%) in the immediate-insertion group and two (4.0%) in the delayed-insertion group (risk ratio, RR 6.86; 95% confidence interval, 95% CI 1.64-28.66). By 1 year the expulsion rates were 17 (33.3%) and six (12.0%) (RR 2.78, 95% CI 1.19-6.47). Following second-trimester MTOP LNG-IUS expulsion rates by 3 months and 1 year were five (18.5%) in the immediate-insertion group and one (3.6%) in the delayed-insertion group (RR 5.19, 95% CI 0.65-41.54). No differences in AEs and bleeding profiles emerged between the groups. CONCLUSIONS: Immediate LNG-IUS insertion after late first- or second-trimester MTOP is feasible, does not increase the complication rate, or alter the uterine bleeding patterns; however, immediate insertion increased the expulsion rate, which may limit the cost-effectiveness. TWEETABLE ABSTRACT: Immediate insertion of LNG-IUS following MTOP at 9-20 weeks of gestation is feasible and safe.

Immediate versus delayed initiation of the levonorgestrel-releasing intrauterine system following medical termination of pregnancy - 1 year continuation rates: a randomised controlled trial.

OBJECTIVE: To assess the 1-year continuation rates and new pregnancies following immediate versus delayed insertion of the levonorgestrel-releasing intrauterine system (LNG-IUS) after medical termination of pregnancy (MTOP) up to 20 weeks of gestation. DESIGN: A randomised controlled trial. SETTING: Helsinki University Hospital, Finland, January 2013 to December 2014. POPULATION: A total of 267 women requesting MTOP and planning LNG-IUS for post-MTOP contraception. METHODS: Insertion of LNG-IUS occurred immediately (0-3 days) or after a delay (2-4 weeks) following MTOP. Follow-up visits were at 3 months and 1 year after MTOP. MAIN OUTCOME MEASURES: LNG-IUS use at 1 year after MTOP. RESULTS: Women were randomised to immediate (n = 134) or delayed (n = 133) insertion of the LNG-IUS, and 133 and 131 were analysed; 127 (95.5%) women received immediate insertion and 111 (84.7%) women had delayed insertion of the LNG-IUS (risk ratio [RR] 1.13, 95% CI 1.04-1.22). The verified numbers of women continuing the LNG-IUS use at 1 year were 83 (62.4%) and 52 (39.7%) (RR 1.57, 95% CI 1.23-2.02). The numbers of new pregnancies were 6 (4.5%) and 16 (12.2%) (RR 0.37, 95% CI 0.15-0.91), and numbers of subsequent TOPs were 4 (3.0%) and 5 (3.8%) (RR 0.79, 95% CI 0.22-2.87). CONCLUSIONS: Immediate insertion of the LNG-IUS following MTOP resulted in higher 1-year continuation rates compared with delayed insertion. In addition, those receiving immediate insertion demonstrated a decreased new pregnancy rate, but no difference in the numbers of another TOP. TWEETABLE ABSTRACT: Immediate LNG-IUS insertion after MTOP results in a higher 1-year continuation compared with delayed insertion.

Bleeding pattern and user satisfaction in second consecutive levonorgestrel-releasing intrauterine system users: results of a prospective 5-year study.

STUDY QUESTION: What is the bleeding pattern during second consecutive levonorgestrel-releasing intrauterine system (LNG-IUS) use? SUMMARY ANSWER: Consecutive use of LNG-IUS is associated with a predictable bleeding pattern, characterized by the absence of the initial period of irregular bleeding seen after interval insertion of an LNG-IUS and a non-bleeding pattern in the vast majority of women. WHAT IS KNOWN ALREADY: With increased popularity of the LNG-IUS for long-term birth control and treatment of heavy menstrual bleeding (HMB), consecutive use of the system is becoming more frequent. One previous study showed 60% amenorrhea rate in consecutive IUS users; however, the sample size was small. STUDY DESIGN, SIZE, DURATION: A prospective multicenter study in four European countries recruited women who wished to continue with LNG-IUS use immediately after the first 5-year period. A total of 204 women were followed up until the end of the first year of the second IUS. Thereafter 170 women continued into the extension phase of the study up to the full 5 years of use of the second IUS and 144 women continued to the end of the study. PARTICIPANTS, SETTING, METHODS: A total of 170 women (mean age 39 years) who had been using their first LNG-IUS for between 4 years 3 months and 4 years 9 months, either for contraception or for treatment of HMB, and who planned to replace the device with a new LNG-IUS, were recruited and followed up to 5 years of the second IUS use. A total of 17 centers in four European countries were involved in the study. Bleeding patterns were analyzed using daily bleeding diaries using 90-day reference periods (RP) for the first year of the second IUS use and for the last RP of each year during Years 2-5 of use. MAIN RESULTS AND THE ROLE OF CHANCE: Approximately 70% of women were free of bleeding during Years 2-5 and up to 49% were amenorrheic. There was a slight increase in the number of bleeding/spotting days of ∼3 days during the first RP immediately after the placement of the second IUS, whereafter the number of bleeding/spotting days returned to the level preceding the second IUS insertion or below that. Absence of bleeding was associated with high overall satisfaction and continuation rates. No serious adverse events assessed as related to the LNG-IUS use occurred during the 5-year period. The cumulative expulsion rate during the 5-year study period was 1.2%. The sample size was large enough to study bleeding patterns, and subjects are likely to represent typical consecutive IUS users, and therefore, the role of chance is small. LIMITATIONS, REASONS FOR CAUTION: The women represent a selected group as they had already successfully used their first IUS for almost 5 years and were willing to continue its use-however, this is currently a common clinical situation. The results may therefore not be extrapolated to first-time users of the LNG-IUS. WIDER IMPLICATIONS OF THE FINDINGS: These data are of importance when counseling women who are making decisions concerning long-term contraception. STUDY FUNDING/COMPETING INTEREST(S): This study was funded by Bayer Pharma AG. P.I. and T.S. are full-time employees of Bayer Pharma AG. O.H. and K. G-D. have received consultancy fees from Bayer Pharma AG. The publication was developed jointly by all authors without third-party involvement and no honoraria were paid for any authors for their contribution to this manuscript. TRIAL REGISTRATION NUMBER: NCT00393198.

ESHRE guideline: management of women with endometriosis.

STUDY QUESTION: What is the optimal management of women with endometriosis based on the best available evidence in the literature? SUMMARY ANSWER: Using the structured methodology of the Manual for ESHRE Guideline Development, 83 recommendations were formulated that answered the 22 key questions on optimal management of women with endometriosis. WHAT IS KNOWN ALREADY: The European Society of Human Reproduction and Embryology (ESHRE) guideline for the diagnosis and treatment of endometriosis (2005) has been a reference point for best clinical care in endometriosis for years, but this guideline was in need of updating. STUDY DESIGN, SIZE, DURATION: This guideline was produced by a group of experts in the field using the methodology of the Manual for ESHRE Guideline Development, including a thorough systematic search of the literature, quality assessment of the included papers up to January 2012 and consensus within the guideline group on all recommendations. To ensure input from women with endometriosis, a patient representative was part of the guideline development group. In addition, patient and additional clinical input was collected during the scoping and review phase of the guideline. PARTICIPANTS/MATERIALS, SETTING, METHODS: NA. MAIN RESULTS AND THE ROLE OF CHANCE: The guideline provides 83 recommendations on diagnosis of endometriosis and on the treatment of endometriosis-associated pain and infertility, on the management of women in whom the disease is found incidentally (without pain or infertility), on prevention of recurrence of disease and/or painful symptoms, on treatment of menopausal symptoms in patients with a history of endometriosis and on the possible association of endometriosis and malignancy. LIMITATIONS, REASONS FOR CAUTION: We identified several areas in care of women with endometriosis for which robust evidence is lacking. These areas were addressed by formulating good practice points (GPP), based on the expert opinion of the guideline group members. WIDER IMPLICATIONS OF THE FINDINGS: Since 32 out of the 83 recommendations for the management of women with endometriosis could not be based on high level evidence and therefore were GPP, the guideline group formulated research recommendations to guide future research with the aim of increasing the body of evidence. STUDY FUNDING/COMPETING INTEREST(S): The guideline was developed and funded by ESHRE, covering expenses associated with the guideline meetings, with the literature searches and with the implementation of the guideline. The guideline group members did not receive payment. All guideline group members disclosed any relevant conflicts of interest (see Conflicts of interest). TRIAL REGISTRATION NUMBER: NA.

Medical versus surgical termination of pregnancy in primigravid women--is the next delivery differently at risk? A population-based register study.

OBJECTIVE: To compare the effect of medical versus surgical termination of pregnancy (TOP), performed in primigravid women, on subsequent delivery. DESIGN: Population-based register study. SETTING: Finland 2000-2009. POPULATION: All primigravid women (n = 8294) who underwent TOP during first trimester of pregnancy by medical (n = 3441) or surgical (n = 4853) method, and whose subsequent pregnancy resulted in singleton delivery. METHODS: The women were identified in the Finnish Register of Induced Abortions, and the data were linked to the Medical Birth and the Hospital Discharge Registries. MAIN OUTCOME MEASURES: Risk of preterm birth, low birthweight, small-for-gestational-age (SGA) infant and placental complications (placenta praevia, placental abruption, retained placenta, placenta accreta). RESULTS: No statistically significant differences in the incidences of preterm birth (4.0% in the medical group versus 4.9% in the surgical group), low birthweight (3.4% versus 4.0%), SGA infants (2.6% versus 2.9%) or placental complications (2.6% versus 2.8%) emerged between the two groups. After adjusting for various background factors, medical TOP was not associated with significantly altered risks of preterm birth (odds ratio [OR] 0.87, 95% confidence interval [95% CI] 0.68-1.13), low birthweight (OR 0.90, 95% CI 0.68-1.19), SGA infant (OR 0.87, 95% CI 0.64-1.20) or placental complications (OR 0.98, 95% CI 0.72-1.34) versus surgical TOP. In a sub-analysis excluding women who underwent surgical evacuation following the index TOP, medical TOP was associated with a reduced risk of preterm birth (P < 0.01), but the difference became insignificant after adjusting for gestational age at the time of TOP, inter-pregnancy interval, maternal age, cohabitation status, socio-economic status, residence and smoking during pregnancy. CONCLUSIONS: A history of one medical versus surgical TOP, performed in primigravid women, is associated with similar obstetric risks in the subsequent delivery.

Trends in teenage termination of pregnancy and its risk factors: a population-based study in Finland, 1987-2009.

STUDY QUESTION: What are the current trends in teenage termination of pregnancy (TOP) and its risk factors? SUMMARY ANSWER: The incidence of teenage TOP fluctuated substantially during the study period and the incidence of repeat TOP among adolescents increased markedly in the 2000s. WHAT IS KNOWN ALREADY: Teenage pregnancy is associated with difficulties in psychological, sexual and overall health. The proportion of teenage pregnancies resulting in termination varies by country and time, but only few countries have reliable statistics on TOPs. STUDY DESIGN, SIZE, DURATION: This nationwide retrospective register study included all the TOPs (n= 52 968) and deliveries (n= 58 882) in Finland between 1987 and 2009 among girls <20 years of age at the beginning of pregnancy. PARTICIPANTS/MATERIALS, SETTING, METHODS: The cohorts were divided into three subgroups; 13-15- (n= 6087), 16-17- (n= 18 826) and 18-19- (n= 28 055) year-olds. MAIN RESULTS AND THE ROLE OF CHANCE: After an initial steady decline, the incidence of teenage TOP increased by 44% between 1993 (8.0/1000) and 2003 (11.5/1000), and thereafter declined by 16% until 2009 (9.7/1000). The incidence was higher in older adolescents, but the trends were alike in all age groups. Early TOPs (performed at <56 days of gestation) more than tripled from 11 to 36% during the study period. However, the proportion of second-trimester TOPs remained steady at ≈ 7%. Young age [13-15 years: odds ratio (OR) 1.75 (95% confidence interval (CI) 1.57-1.94), 16-17 years: OR 1.13 (1.05-1.23), 18-19 years: OR 1 (reference category)] and non-use of contraception [(OR 11.16 (10.15-12.27)] were related to a higher risk of second-trimester TOP. The incidence of repeat TOP increased by 95% from 1.9/1000 to 3.7/1000 in 18-19-year-olds and by 120% from 0.5/1000 to 1.1/1000 in 16-17-year-olds between 1993 and 2009. Increasing age [13-15 years: OR 0.16 (95% CI 0.14-0.19), 16-17 years: OR 0.49 (0.45-0.52), 18-19 years 1 (Ref)], living in an urban area [rural: OR 0.62 (0.56-0.67), urban: OR 1 (Ref)] and having undergone a second-trimester TOP [OR 1.46 (1.31-1.63)] were risk factors for repeat TOP. The planned use of intrauterine contraception for post-abortal contraception increased from 2.6 to 6.2% and among girls with repeat TOP from 10 to 19%. LIMITATIONS: The retrospective nature of the study remains a limitation and the quality of the data is reliant on the accuracy of reporting. We were not able to link repeat TOPs of the same woman in our data set. However, the share of repeat abortions was moderate. WIDER IMPLICATIONS OF THE FINDINGS The rate of teenage TOP seems to rapidly reflect changes in national sexual and reproductive health services and policy. The rising rate of repeat TOP is alarming and may represent a sign of marginalization among these girls. All efforts to maintain a low rate of teenage pregnancy are welcomed.

Hormonal contraception and mental health: results of a population-based study.

BACKGROUND: The effects of oral contraceptives (OCs) on mental health are not clear, and no study has been focused on the effects of the levonorgestrel-releasing intrauterine system (LNG-IUS) on mental health. The aim of this study was to analyse the association between the use of OCs and the LNG-IUS and psychological well-being and psychopathology. METHODS: The associations between the current use of OCs and the LNG-IUS, and their duration versus mood symptoms [Beck Depression Inventory (BDI)], psychological well-being [(General Health Questionnaire-12 (GHQ-12)] and recent psychiatric diagnoses [(Composite International Diagnostic Interview (CIDI)] were examined among women who participated in the Finnish-population-based Health 2000 study. Analyses were performed on the 30- to 54-year-old sample (n = 2310); some of the analyses were extended to include the younger age group (18- to 54-year-old sample; n = 3223). RESULTS: Overall, hormonal contraception was well tolerated with few significant effects on psychological well-being. The length of OC use was inversely associated with some BDI items ('dissatisfaction, irritability, lost interest in people, earlier waking and lost interest in sex'), and directly associated with 'worries about one's health' (BDI) and with a current diagnosis of 'alcohol dependence' (CIDI). The current use of the LNG-IUS was inversely associated with 'earlier waking' (BDI) and with 'impaired concentration' (GHQ), while the length of LNG-IUS use was inversely associated with 'strain' (GHQ). CONCLUSIONS: The influence of hormonal birth control on mental health is modest and mainly favourable. The length of current OC use seems to have some beneficial effects on mood although the longer the duration of use, the greater the association with a diagnosis of alcohol dependence. Knowledge of the use of hormonal contraception might be of value when assessing psychopathology in women. The cross-sectional design, with partly retrospective data collection, precludes any causal conclusions.

Predictors of bleeding and user satisfaction during consecutive use of the levonorgestrel-releasing intrauterine system.

BACKGROUND: Consecutive use of the levonorgestrel-releasing intrauterine system (LNG-IUS) is increasing. However, little is known about factors that predict the bleeding during consecutive use. The objective of this study was to analyse the possible factors which may predict the bleeding pattern during the first year of use of a second LNG-IUS. METHODS: Fertile-aged women (n = 204) who had used their first LNG-IUS for over 4 years and who opted for a second LNG-IUS were recruited. Bleeding data were reported using 90-day reference periods (RPs) starting from the last 90 days of the first LNG-IUS use (baseline), until the end of the first year of the second LNG-IUS (RPs 1-4). RESULTS: Demographic factors such as age, parity, body mass index, indication of LNG-IUS use or smoking could not be identified as predictors for bleeding and spotting (B/S). Mean (+/-SD) number of B/S days was 8.9 (+/-9.1) at baseline. This increased slightly during RP1 and fell to 6.4 (+/-8.1) during RP4. Compared with the mean, women with uterine fibroids or a bleeding pattern of >9 days of spotting or any bleeding at RP1 had more B/S days during RP1-4. Although the number of B/S days decreased progressively from RP1 to RP4 in the group with a bleeding pattern of >9 days of spotting or any bleeding at baseline, such a phenomenon was not observed for women with fibroids. The difference for the change in B/S days between women with and without fibroids was statistically significant at RP3 and RP4. A high degree (91.7%) of satisfaction with the bleeding pattern was observed, with amenorrhoeic women being most satisfied. CONCLUSIONS: Uterine B/S is reduced during consecutive use of the LNG-IUS. Women with uterine fibroids or any bleeding at baseline continued to have more B/S than other women.

Bleeding pattern and safety of consecutive use of the levonorgestrel-releasing intrauterine system (LNG-IUS)--a multicentre prospective study.

BACKGROUND: The LNG-IUS has increasingly been used for contraception, treatment of menorrhagia and endometrial protection during hormone replacement therapy since mid-1990s. Thus, many women use the LNG-IUS consecutively. However, published data on the bleeding pattern regarding consecutive use of the LNG-IUS is scarce. METHODS: We performed a prospective 15-month multicentre study on the bleeding profile, removal and insertion procedures and safety of the second LNG-IUS in fertile-aged women who had used their first LNG-IUS between 4 years 3 months and 4 years 9 months and who opted for the insertion of a second IUS immediately after removal of the first IUS. Bleeding data were reported descriptively starting from the last 90 days of the first IUS use and continuing for up to 1 year. RESULTS: Of the 234 subjects screened, 204 (87%) entered the trial. The median number of bleeding/spotting days during the last 90 days of the first LNG-IUS was 7 (25 and 75% percentiles 0 and 15). Due to bleeding associated with the insertion procedure, this increased to 8 days (4 and 18) during the first 90-day reference period, thereafter decreasing to 4 (0 and 10) days during the second to fourth reference periods. Only one expulsion and no pregnancies, pelvic inflammatory diseases or perforations occurred. A total of 12 subjects (5.9%) prematurely discontinued the study: five due to an adverse event and seven due to other reasons (inclusive of loss to follow-up). CONCLUSIONS: This study confirms the favourable bleeding profile and safety of consecutive use of the LNG-IUS.

Foley catheter induction of labor as an outpatient procedure.

OBJECTIVE: The aim of our study was to introduce outpatient induction of labor by Foley catheter, and to compare outcomes and preferences between in-patients and outpatients. STUDY DESIGN: This clinical cohort study was conducted in Helsinki University Hospital between January 2011 and January 2012. A total of 485 women scheduled for induction of labor by Foley catheter were included. The main outcome measures were cesarean delivery rate, and maternal and neonatal infectious morbidity. Maternal satisfaction of outpatients was measured after delivery. RESULTS: Two hundred and four (42.1%) women were managed as outpatients and 281 (57.9%) women as in-patients. The rates of cesarean delivery, and maternal or neonatal infections did not differ between outpatients and in-patients. Of the outpatients, 85.3% were satisfied. CONCLUSION: Induction of labor by Foley catheter appears suitable for outpatients, and resulted in no differences in cesarean delivery or infection rates compared with in-patients. Most women were satisfied with the outpatient induction.

Distribution of RU 486 and its demethylated metabolites in humans.

The concentrations of RU 486 and its demethylated metabolites were determined by RIA in samples of myometrium, abdominal adipose tissue, and serum, which were collected at hysterectomies performed 12-15 h after oral administration of 200 mg RU 486. The RU 486 concentrations in myometrium were similar in the five women studied, with a mean of 148 +/- 58 (+/- SD) ng/g (344 +/- 135 pmol/g). The adipose tissue RU 486 levels varied more, the mean concentration being 447 +/- 191 ng/g (1041 +/- 445 pmol/g). The serum RU 486 concentrations ranged from 175-899 ng/ml [mean, 396 +/- 259 ng/mL (922 +/- 603 nmol/L)]. In these women the nonprotein-bound fraction of [6,7-3H]RU 486 varied from 1.4-3.1% (mean, 2.3%). The approximate concentrations of the combined mono- and didemethylated metabolites of RU 486 were 1.4, 3.1, and 5.2 times higher in adipose tissue, myometrial tissue, and serum, respectively, than those of the parent RU 486. In vitro, rapid and nonsaturable accumulation of [6,7-3H]RU 486 from phosphate buffer into adipose tissue was inhibited by the addition of alpha 1-acid glycoprotein, the specific serum transport protein for RU 486, to the buffer medium. Accumulation of [6,7-3H]RU 486 in myometrial specimens was poor. The enterohepatic cycling of RU 486 was assessed in four normal subjects by repetitive intake of charcoal subsequent to ingestion of 200 mg RU 486. Compared to other normal subjects, the serum levels and areas under the concentration curves were lower and t1/2 values shorter in the group given charcoal, suggesting that in vivo RU 486 may be partly pooled in the enterohepatic cycle. Our studies suggest that despite the low volume of distribution and the effective serum binding of RU 486, the myometrial and adipose tissue concentrations of RU 486 and its metabolites were similar (approximately 10(-9)-10(-10) mol/g) after oral intake of RU 486.